Bradykinin B 2 and GPR100 receptors: a paradigm for receptor signal transduction pharmacology

The aim of the present report was to investigate the ligand selectivity of the human orphan G‐protein‐coupled receptor GPR100 (hGPR100), recently identified as a novel bradykinin (BK) receptor, as compared with that of the human B 2 receptor (hB 2 R) stably transfected in Chinese hamster ovary cells. BK was able to inhibit the cAMP production induced by forskolin with a potency 100‐fold lower at the hGPR100 (pEC 50 =6.6) than that measured at the hB 2 R (pEC 50 =8.6). Both effects were inhibited by the B 2 receptor antagonist Icatibant (1 μ M ). The nonpeptide B 2 receptor agonist FR190997 (8‐[2,6‐dichloro‐3‐[ N ‐methylcarbamoyl)cinnamidoacetyl]‐ N ‐methylamino]benzyloxy]‐2‐methyl‐4‐(2‐pyridylmethoxy)quinoline) did inhibit the forskolin‐induced cAMP production (pEC 50 =7.7) at the hB 2 R, whereas it was not able to exert any effect at the hGPR100. The human insulin‐like peptide relaxin 3 did inhibit the cAMP production at the hGPR100 (pEC 50 =7.3) at a greater extent than BK, and was devoid of any effect at the hB 2 R. FR190997 and relaxin 3 responses at the hB 2 R and hGPR100, respectively, were not inhibited by Icatibant (1 μ M ). These data indicate FR190997 and relaxin 3 as selective agonists for hB 2 R and hGPR100, respectively, and support the concept that different agonists may specifically bias the conformational states of a receptor to result in a final common G protein coupling, which is differentially recognized by antagonists. British Journal of Pharmacology (2004) 143 , 938–941. doi: 10.1038/sj.bjp.0706025